validation of a developed tool to identify compatibility of drug-drug
TRANSCRIPT
VALIDATION OF A DEVELOPED TOOL TO
IDENTIFY COMPATIBILITY OF DRUG-DRUG
AND DRUG-PARENTERAL NUTRITION IN
NEONATES AND EVALUATION OF CLINICAL
OUTCOME OF THE ADMINISTRATION OF THE
IV DRUGS AND PARENTERAL NUTRITION
YELLY OKTAVIA SARI
UNIVERSITI SAINS MALAYSIA
2016
VALIDATION OF A DEVELOPED TOOL TO
IDENTIFY COMPATIBILITY OF DRUG-DRUG
AND DRUG-PARENTERAL NUTRITION IN
NEONATES AND EVALUATION OF CLINICAL
OUTCOME OF THE ADMINISTRATION OF THE
IV DRUGS AND PARENTERAL NUTRITION
by
YELLY OKTAVIA SARI
Thesis submitted in fulfillment of the requirements
for degree of Doctor of Philosophy
February 2016
ii
ACKNOWLEDGEMENT
Above of all, I thank Allah the Almighty, the most Gracious and the most
Merciful for blessing me with good physical health, sensible mind and
appropriate attitude that I was able to pursue my study and complete this
doctoral thesis without any major obstacle.
I would like to express my gratitude to my Supervisor Professor Dr. Mohd.
Baidi Bahari and my co-Supervisor Dr. Baharudin Ibrahim for his ideas and
suggestions in the planning and execution of the research as well as the thesis
writing process. I value their sincere understanding, continuous support and
guidance that inspire me to move forward and persevere in different
situations.
Lastly, I am thankful to my family who provide me with unconditional love
and support that enabled me to overcome any obstacles or demand during the
long and arduous journey of this doctoral programme. I am also grateful to
my friends for their encouragement and belief in my ability to accomplish my
goals.
Yelly Oktavia Sari
iii
TABLE OF CONTENTS
Page
ACKNOWLEDGEMENT ..................................................................................... ii
TABLE OF CONTENTS ....................................................................................... iii
LIST OF FIGURES ................................................................................................ x
LIST OF TABLES ................................................................................................. xi
LIST OF APPENDICES ...................................................................................... xiv
LIST OF ABBREVIATIONS ............................................................................... xv
ABSTRAK ........................................................................................................... xvi
ABSTRACT ......................................................................................................... xix
CHAPTER 1: INTRODUCTION ........................................................................ 1
1.1 Background ....................................................................................................... 1
1.2 Parenteral Nutrition in Malaysia ....................................................................... 4
1.3 Problem Statement ............................................................................................ 5
1.4 Objectives of the Study ..................................................................................... 7
1.5 Hypothesis of the Study .................................................................................... 8
1.6 Significance of the Study .................................................................................. 9
CHAPTER 2: LITERATURE REVIEW .......................................................... 10
2.1 Nutritional Support ......................................................................................... 10
2.1.1 Oral Nutrition ........................................................................................ 10
2.1.2 Enteral Nutrition ................................................................................... 10
2.1.3 Parenteral Nutrition ............................................................................... 11
iv
2.1.4 Parenteral Nutrition in Adult ................................................................ 12
2.1.5 Parenteral Nutrition in Pediatric ........................................................... 14
2.1.6 Parenteral Nutrition in Neonates ........................................................... 15
2.1.7 Component of Parenteral Nutrition ....................................................... 18
2.1.7 (a) Fluid ....................................................................................... 22
2.1.7 (b) Macronutrient ......................................................................... 22
(i) Carbohydrate ................................................................... 23
(ii) Protein ............................................................................ 25
(iii) Fat.................................................................................. 28
2.1.7 (c) Micronutrient.......................................................................... 30
(i) Electrolytes ...................................................................... 30
(ii) Major Minerals ............................................................... 31
(iii) Trace Minerals .............................................................. 31
(iv) Vitamin .......................................................................... 34
2.1.8 Complication Associated with Parenteral Nutrition ................................. 36
2.1.8 (a) Mechanical ............................................................................. 36
2.1.8 (b) Metabolic ............................................................................... 37
2.1.8 (c) Infections ................................................................................ 40
2.1.9 Monitoring Parenteral Nutrition Efficacy ................................................. 41
2.1.10 Administration of Drug with Parenteral Nutrition .................................. 43
2.1.11 Compatibility of Injectable Drug and Parenteral Nutrition..................... 47
2.1.12 Incompatibilities and Interactions of Drug with Parenteral Nutrition .... 49
2.1.12 (a) Emulsion Changes ................................................................ 50
2.1.12 (b) Incompatibilities with the Bag Material .............................. 51
2.1.12 (c) Inactivation of Drugs or Parenteral Nutrition Components . 52
v
2.1.12 (d) Degradation Reactions Leading to Potential Activity ......... 52
2.2 Drug Nutrient Interaction ................................................................................ 53
2.3 Computer Application for Nutrient-Drug Interaction Management ............... 57
2.3.1 Decision Support and Clinical Alert Systems in Drug Nutrient
Interaction ......................................................................................... 58
2.3.2 Clinical Decision Support System for Neonatal Care ........................... 59
2.4 Development of Database My. Drug Compatibility Checker (My.DCC) ...... 62
2.4.1 Introduction......................................................................................... 62
2.4.2 Supporting Tools to Prevent Drugs Incompatibilities in Pediatric and
NICU .................................................................................................. 63
2.4.3 Information Technology in Health the Malaysian Context ................ 66
CHAPTER 3: METHODOLOGY ..................................................................... 69
3.1 Introduction ..................................................................................................... 69
3.2 Part I, Evaluation of Clinical Outcome of Parenteral Nutrition Practices ...... 69
3.2.1 Study Design ....................................................................................... 69
3.2.2 Study Time and Location.................................................................... 69
3.2.3 Population and Sampling Procedure ................................................... 70
3.2.4 Inclusion Criteria ................................................................................ 70
3.2.5 Exclusion Criteria ............................................................................... 70
3.2.6 Patient Data Collection Form ............................................................. 71
3.2.6 (a) Demographic Data and Birth History .................................. 71
3.2.6 (b) Disease and Treatment......................................................... 71
3.2.6 (c) Intravenous Administration Data ......................................... 71
3.2.6 (d) Laboratory Test.................................................................... 72
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3.2.7 Ethical Clearance ................................................................................ 72
3.2.8 Data Collection Procedure .................................................................. 72
3.2.9 Data Analysis ...................................................................................... 73
3.2.10 Study Flowchart ................................................................................ 73
3.3 Part II, Development of My.DCC Database ................................................... 75
3.3.1 Introduction......................................................................................... 75
3.3.1 (a) Phase 1: Identify and Collecting the Compatibility
Information of Drug –Drug and Drug - Parenteral
Nutrition .............................................................................. 75
3.3.1 (b) Phase 2: Develop Database.................................................. 77
3.3.2 Tools Used in Development of My.DCC ........................................... 78
3.3.3 Concept and Design ............................................................................ 79
3.3.4 Design of Information Systems .......................................................... 79
3.3.4 (a) Conceptual Design ............................................................... 80
3.3.4 (b) Physical Design ................................................................... 80
3.3.5 System Design Tools .......................................................................... 81
3.3.5 (a) Data Flow Diagrams (DFD) ................................................ 81
3.3.5 (b) Entity Relationship Diagram (ERD).................................... 81
(i) Entities ......................................................................... 82
(ii) Attributes ..................................................................... 82
(iii) Relation ....................................................................... 82
3.3.5 (c) Hierarchy Process Input Output (HIPO) .............................. 83
3.3.6 Design of My.DCC ............................................................................. 83
3.3.6 (a) General Design .................................................................. 83
3.3.6 (b) Data Flow Diagrams (DFD) .............................................. 83
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(i) Context Diagram……………………………………..83
(ii) Entity Relationship Diagram (ERD)………………..84
(iii) Hierarchy Process Input Output (HIPO)…………...87
3.3.7 Validation of My.DCC………………………………………………87
3.3.7 (a) Validation of Content…………………………………....87
3.3.7 (b) Validation in Practice…………………………………….88
CHAPTER 4: RESULT…………………………………………….…………..89
4.1 Introduction…………………………………………………………………..89
4.2 Evaluation………………………………………………………………........89
4.2.1 Demographic Data…………………………………………………...89
4.2.2 Birth Characteristic in Study Population…………………………….91
4.2.3 Parenteral Nutrition Practices in NICU Patients…………………….97
4.2.4 Clinical Evaluation of NICU Patients……………………………....103
4.3 Development and Validation of My. DCC………………………………….118
4.3.1 Identification of IV Drugs Commonly Prescribed in NICU……....118
4.3.2 Detailed Design of My. DCC Database…………………………...120
4.3.2 (a) Output Design………………………………………….120
4.3.2 (b) Input Design……………………………………………121
4.3.3 Validation of My. DCC Database………………………………....123
4.3.3 (a) Time Validation to Retrieve the Data…………….……123
4.3.3 (b) Validation of My. DCC Reporting System……………125
4.4 Evaluation of Clinical Outcome in Patient with Incompatible
Interaction…………………………………………………………………...130
4.4.1 Incompatibility of Drug – Drug and
Drug - Parenteral Nutrition……………………………………….130
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4.5 Comparison of Clinical Outcome in Patient with Incompatible and
Compatible Interaction……………………………………………………...138
CHAPTER 5: DISCUSSION……………………………………………….…144
5.1 Introduction…………………………………………………………… ……144
5.2 Evaluation of Clinical Outcomes of Parenteral Nutrition
in NICU Patients……………………………………………………………144
5.3 Validation of a Developed Database My.Drug Compatibility
Checker (My.DCC)………………………………………………………….151
5.4 Evaluation of Clinical Outcome of patients with Incompatible Interaction
of Pediatric Injectable Drugs and Parenteral Nutrition…………………….154
CHAPTER 6: CONCLUSION, LIMITATION AND
RECOMMENDATION……………………………………………………….157
6.1 Conclusion……………………………………………………………….....157
6.2 Limitation of the Study……………………………………………………..158
6.3 Recommendations………………………………………………………….158
REFERENCES ………………………………………………………………...159
APPENDIX A…………………………………………………………………..184
APPENDIX B…………………………………………………………………..185
APPENDIX C…………………………………………………………………..186
APPENDIX D…………………………………………………………………..187
APPENDIX E…………………………………………………………………..188
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APPENDIX F…………………………………………………………………..189
APPENDIX G………………………………………………………………….190
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LIST OF FIGURE
Page
Figure 2.1 Incompatibility reactions in Parenteral Nutrition…………………….50
Figure 3.1 Study Flowchart. .................................................................................. 74
Figure 3.2 Storyboard of Development Database. ................................................ 77
Figure 3.3 Summary of Development of Database. .............................................. 78
Figure 3.4 Diagrammatic Presentation of Tools and Requirement for Access. .... 78
Figure 3.5 Context Diagram of My.DCC.............................................................. 84
Figure 3.6 Entity Relationship Diagram (ERD) of My.DCC. .............................. 86
Figure 3.7 Hierarchy Input Process Output (HIPO) of My.DCC. ........................ 87
Figure 4.1 Drug Compatibility Result of My.DCC. ........................................... 120
Figure 4.2 Drug Compatibility Result of Patient Treatment ............................... 121
Figure 4.3 Section to Update / Input of a New Drug Information ...................... 121
Figure 4.4 Section with Compatibility Information of Drugs in Syringe ........... 122
Figure 4.5 Section with Compatibility Information of Drugs in
Y-site Injection ................................................................................ .122
Figure 4.6 Section to Update/Input of a New Patient ......................................... 123
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LIST OF TABLE
Page
Table 2.1 Indications for PN Support and Route of Administration for
Neonates Who Require Intensive Care……………………………….17
Table 2.2 Usual Daily Requirements of Nutrients in PN Solutions for
Preterm and Term Neonates………………………………………….18
Table 2.3 Amounts of Trace Minerals Recommended for Term and Preterm Infants
in Total Parenteral Solutions (PN)……………………………………33
Table 2.4 Amounts of Vitamins Recommended for Term and Preterm Infants in PN
Solutions Compared to PrescribedDosages of MVI-Pediatric..............35
Table 2.5 Nutritional Evaluation Parameters for Patients Receiving Parenteral
Nutrition………………………………………………………………42
Table 2.6 Metabolic Monitoring for Patients Receiving Parenteral Nutrition…..43
Table 2.7 Y-injection site Compatibility of Medications with
Parenteral nutrition…………………………………………………...46
Table 2.8 Incompatibility Reactions…………………………………………….49
Table 2.9 Summary of the Articles that Described Drug-Nutrient Interactions...55
Table 2.10 Summary of Different Supporting Tools to Identify
The Compatibility of Pediatric Injectable Drugs…………………….65
Table 3.1 Self-developed Excel sheet of all the Pediatric Injectable Drugs and
Compatibility Information……………………………………………76
Table 3.2 Injectable Drug Used among NICU patients in Hospital Pulau
Pinang………………………………………………………………...76
Table 3.3 Symbols of DFD (Data Flows Diagram)………………………...……81
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Table 4.1 Socio demographic Characteristic of the Study Population………...90
Table 4.2 Birth Characteristic of the patients………………………………….91
Table 4.3 Comparison of Gender Differences among Various Variable of
Birth History (n=234)………………………………………………93
Table 4.4 Comparison of Race with Various Variable of
Birth History (n=234)………………………………………………95
Table 4.5 Comparison of Gestational Age and Various Variable of
Birth History (n=234)………………………………………………96
Table 4.6 Comparison of Birth Weight with Various Variable of
Birth History (n=234)………………………………………………97
Table 4.7 Descriptive of Parenteral Nutrition Practices among
Study Population (n=234)………………………………………….98
Table 4.8 Comparison of Parenteral Nutrition Practices and
Gestational Age (n=234)………………………………………….100
Table 4.9 Comparison of Parenteral Nutrition Practices and
Birth Weight (n=234)……………………………………………..102
Table 4.10 Concurrent Medical Problems among NICU Patients (n=234)….103
Table 4.11 Association between Gender and Concurrent Medical Problem
among Patients (n=234)…………………………………………..107
Table 4.12 Association between Race and Concurrent Medical Problem
among Patients (n=234)…………………………………………110
Table 4.13 Association between Gestational and Concurrent Medical
Problem among Patients (n=234)………………………………..113
Table 4.14 Association between Birth Weight and Concurrent Medical Problem
among Patients (n=234)…………………………………………116
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Table 4.15 Descriptive Distribution of Intravenous Drugs Given during
Parenteral Nutrition Administration. ..................................................... 119
Table 4.16 Comparison of the Time to Retrieve the Data. ...................................... 124
Table 4.17 Compatibility Information of Injectable Drugs with Parenteral Nutrition
Administration using My.DCC. ............................................................. 126
Table 4.18 Compatibility Information of Drug – Drug Interaction in Syringe and Y-
site Administration using My.DCC. ...................................................... 127
Table 4.19 Compatibility Information of Injectable Drugs Combination in NICU. 130
Table 4.20 Evaluation of Incompatibility Drug - Parenteral Nutrition (2-in-1) in Y-
site Administration ................................................................................. 131
Table 4.21 Evaluation of Incompatibility Drug – Drug Combination in Y-site
Administration…………………………………………………………135
Table 4.22 Evaluation of Incompatibility of Drug-Drug Combination
in Syringe…………………………………….. …………………........137
Table 4.23 Demographic of Patients………………………………………………139
Table 4.24 Comparison of Patient Clinical Diagnosis…………………………….140
Table 4.25 Comparison of Parenteral Nutrition Practices………………………....141
Table 4.25 Comparison of Renal Function and Liver Function between
Compatible and Incompatible Group…………………………………143
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LIST OF APPENDICES
Page
Appendix A: Study Approval………………………………………………...…..184
Appendix B: Patient Data Collection Form………………………………..…...185
Appendix C: Letter of Agreement……………………………………………....186
Appendix D: Manual of My.DCC…………………………………………...….187
Appendix E: My.DCC database………………………………………………...188
Appendix F: Certificate of Proofreading..………………..……………………..189
Appendix G: Publication List………………………...…………………………190
xv
LIST OF ABBREVIATION
CNS Central Nervous System
CPAP Continuous Positive Airway Pressure
DIVC Disseminated Intra-Vascular Coagulation
ELBW Extremely Low Birth Weight
G1P0 Gravida 1 Parity 0
G2P1 Gravida 2 Parity 1
G3P2 Gravida 3 Parity 2
HFOV High Frequency Oscillatory Ventilation
HFPV High Frequency Positive Ventilation
IMV Intermittent Mandatory Ventilation
IVH Intra Ventricular Haemorrhage
MVI Multi Vitamin Injection
PDA Patent Ductus Arterious
RDS Respiratory Distress Syndrome
SGA Small in Gestational Age
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PENGESAHAN ALAT YANG DIBANGUNKAN UNTUK MENGENALPASTI
KESERASIAN UBAT-UBAT DAN UBAT-NUTRISI PARENTERAL PADA
NEONAT DAN PENILAIAN HASIL KLINIKAL PEMBERIAN
UBAT IV DAN NUTRISI PARENTERAL
ABSTRAK
Pemberian ubat intravena di dalam Unit Rawatan Rapi Neonatal (NICU)
adalah kritikal kerana kesulitan akses vena, polipengubatan, penghadan cecair dan
kadar infusi yang rendah. Apabila Nutrisi Parenteral (PN) diinfusi secara intravena,
ini telah dianggap sebagai pembawa kepada ubat. Ubat-ubatan boleh ditambah
kepada formulasi PN dalam usaha untuk mengurangkan keperluan cecair,
mengurangkan keperluan suntikan tapak-Y dan mengurangkan potensi kontaminasi
salur akibat manipulasi serta mengurangkan masa yang diperlukan untuk menyuntik
ubat. Walau bagaimanapun, risiko tetap tinggi akibat kekurangan maklumat tentang
keserasian fizikokimia ubatan. Kajian ini bertujuan untuk menilai hasil klinikal
pemberian drug IV dan PN di kalangan pesakit neonat yang menerima PN semasa
dirawat di dalam hospital dan untuk membangunkan pangkalan data tentang
keserasian drug-drug dan drug-larutan PN. Satu bentuk kajian Keratan Rentas
Restrospektif telah digunapakai untuk menjalankan kajian ini. Subjek penyelidikan
ini adalah pesakit neonat yang menerima PN di dalam Unit Rawatan Rapi Neonatal
(NICU) Hospital Pulau Pinang, Malaysia. Subjek kajian merangkumi semua pesakit
yang dimasukkan ke wad NICU daripada Januari 2008 hingga Disember 2009.
Prosedur pensampelan adalah secara Pensampelan Umum dengan mengumpulkan
semua rekod pesakit yang memenuhi kriteria kemasukan dan kriteria pengecualian
yang ada. Sejumlah 234 bayi baru lahir yang telah memenuhi kriteria dimasukkan ke
dalam kajian ini. Borang pengumpulan data dihasilkan penyelidik, telah digunapakai
xvii
dan hanya seorang pemungut data yang mengumpulkan data kajian. Kelulusan etika
telah diperoleh dari institusi tempatan (Jawatankuasa Penyelidikan Klinikal, CRC)
dan daripada Jawatankuasa Etika Penyelidikan Kementerian Kesihatan (MREC).
Data dianalisa secara statisk menggunakan Statistic Package for Social Science 15.0
(SPSS 15.0). Kesemua 234 (100%) pesakit yang dimasukkan ke NICU Hospital
Pulau Pinang dimasukkan ke dalam kajian ini. Daripada jumlah ini, majoriti 123
(52.6%) adalah perempuan dan selebihnya (47.4%) adalah lelaki. Taburan etnik
menunjukkan Melayu mendominasi dengan 158 (67.5%) diikuti dengan Cina 41
(17.5%), India 23 (9.8%) dan lain-lain 12 (5.1%). Kebanyakan pesakit, 98 orang
(41.8%) telah dilahirkan pada 28-31 minggu kandungan and 156 (66.67%)
mempunyai berat badan di antara julat 1001-2000 gram. Ciri-ciri berkaitan pesakit
(berat lahir, umur kandungan, mod kelahiran dan kaum-etnik) mempunyai perkaitan
yang signifikan dengan amalan PN dan hasil klinikal. Satu pangkalan data
dibangunkan iaitu “My. Drug Compatibility Checker (My.DCC)” yang memberikan
maklumat keserasian berkaitan dengan interaksi drug-drug dan drug-PN bagi drug-
drug IV yang sering dipreskrib untuk pesakit NICU. Pangkalan data My.DCC adalah
alat yang sahih dan dipercayai untuk memberikan maklumat berkaitan keserasian dan
interaksi drug-drug di dalam bahan tambahan larutan nutrisi parenteral. Konsep,
rekabentuk dan isi kandungan yang diperlukan untuk prototaip ini telah dikaji,
dikumpulkan dan disediakan oleh penyelidik. Seorang juru analisa sistem terlibat
untuk membantu membangunkan peangaturcaraan sistem. Sebanyak 29 drug
suntikan telah dianalisa menggunakan My.DCC. Pangkalan data ini telah digunakan
untuk menyemak keserasian daripada kombinasi rawatan ubatan yang diterima oleh
pesakit semasa di NICU Hospital Pulau Pinang. Penemuan My.DCC menunjukkan
daripada 29 drug yang diberikan kepada pesakit; 4 kombinasi ubat adalah serasi di
xviii
dalam picagari, 2 kombinasi drug tidak serasi di dalam picagari, 25 kombinasi drug
serasi dalam suntikan tapak-Y dan 8 drug tidak serasi dalam suntikan tapak-Y. Di
kalangan pesakit, 19 neonat telah mengalami masalah keserasian interaksi drug-drug
dan drug-nutrisi parenteral. Pengenalpastian interaksi drug-drug dan drug-nutrien
dapat membantu ahli perubatan untuk mengelakkan komplikasi dan mencapai hasil
yang disasarkan.
xix
VALIDATION OF A DEVELOPED TOOL TO IDENTIFY COMPATIBILITY
OF DRUG - DRUG AND DRUG - PARENTERAL NUTRITION
IN NEONATES AND EVALUATION OF CLINICAL OUTCOME OF THE
ADMINISTRATION OF THE IV DRUGS AND PARENTERAL NUTRITION
ABSTRACT
Intravenous drug administration in neonatal intensive care unit (NICU) is
critical because of poor venous access, polymedication, fluid restriction and low
infusion rate. Since parenteral nutrition (PN) is infused intravenously, it is often
considered as a vehicle for medication administration. Medications may be added to
PN formulations in an effort to decrease fluid requirements, reduce the need for Y-
site injections, reduce the possibility of line contamination due to manipulation and
decrease labor time required for drug administration. Risk is further increased by
inadequate information on the physicochemical compatibility of drugs. This study
aimed to evaluate clinical outcome of the administration of IV drugs and PN among
neonates patients who had received PN during their hospitalization and to develop a
data base on compatibility of drug-drug and drug-PN solution. A cross-sectional
retrospective study design has been adopted to conduct this study. Subjects of this
research were neonates’ patients receiving PN in Neonatal Intensive Care Unit
(NICU) Hospital Pulau Pinang, Malaysia. Study subjects were all patients admitted
in NICU from January 2008 until December 2009. Sampling procedure was
universal sampling by collecting all available patients’ medical record that met our
inclusion and exclusion criteria. A total of 234 newborn met the study criteria were
included in this study. Self-developed data collection form was used with only single
data collector for data collection. Approval for ethical clearance was obtained from
xx
the local institutions (Clinical Research Committee, CRC) and from the Ministry of
Health Research Ethics Committee (MREC). Data was statistically analyzed using
Statistic Package for Social Science 15.0 (SPSS 15.0). All 234 (100%) patients
admitted to NICU Hospital Pulau Pinang were included. Among them, majority 123
(52.6%) were females and the rest 111 (47.4) were males. Ethnic distribution showed
predominance of Malay with 158 (67.5%) followed by Chinese 41 (17.5%), Indian
23 (9.8%) and 12 (5.1%) others. Most of the patients; 98 (41.8%) were born at 28-31
weeks of gestation and 156 (66.67%) were in the body weight range of 1001-2000
grams. Patient related characteristics (birth weight, gestation age, mode of delivery
and ethnicity) have significant association with PN practices and clinical outcomes.
A developed database “My. Drug Compatibility Checker (My.DCC)” will provide
the compatibility information related to drug-drug and drug-PN interaction among IV
drugs commonly prescribed in NICU patients. Database My.DCC consider as
validate and reliable tool to provide information regarding compatibility and drug-
drug interactions of admixture in parenteral nutrition solutions. The concept, design
and contents required for this prototype were researched, collected and provided by
researcher. One systems analyst was involved to carry out the programming of the
system. The 29 injectable drugs had been analyzed with My.DCC. The database was
used to check the possible compatibility of medication combination received during
patient’s treatment in NICU Hospital Pulau Pinang. The My.DCC finding showed
that among 29 drugs that administered to the patients; 4 drugs combination were
compatible in syringe, 2 drugs combination were incompatible in syringe, 25 drugs
combination were compatible in Y-site injection and 8 drugs were incompatible in
Y-site injection. Among them 19 neonates had incompatible interaction of drug-drug
and drug-parenteral nutrition interaction. Recognition of these drug-drug and drug-
xxi
nutrient interactions may assist the clinician to prevent complications and to achieve
desired therapeutics outcomes.
1
CHAPTER I
INTRODUCTION
1.1 Background
The standard use of parenteral nutrition (PN) in clinical practice started in 1968, after
Dudrick et al., efforts. These pioneers explained that parenteral therapy of amino acids
and glucose concentrated solutions together with minerals, vitamins and
micronutrients may result in more growth in children and adults. Initially PN
admixtures were administered mostly with amino acids and glucose. Now, PN includes
intravenous administration of amino acids, glucose, lipids, electrolytes, vitamins and
trace elements (Dudrick, 2009, Waitzberg et al., 2006).
Patients who are receiving PN often need to receive parenteral medications as well.
Questions about parenteral drug compatibility with PN have arisen with some
frequency (Joy et al., 2010). Unfortunately, split administration is not always feasible.
The line being used to administer PN constantly may be the only IV access accessible
(Mirtallo, 2004). On the other hand, even if multiple lumen catheters are used, the
numbers of parenteral doses required in high-intensity therapeutic situations, such as
cancer treatment or intensive care may make simultaneous administration with a PN
admixture (Hoang et.al 2008; Kearney et.al., 1998).
PN is a lifesaving medical intervention for many pediatric patients as PN provides
energy for growth and tissue repair when the gastrointestinal tract cannot be used due
to small stomach capacity, immature gastrointestinal tract and illnesses. This is
2
especially true for preterm or low birth weight neonates who represent the highest
percentage of the pediatric population requiring parenteral nutrition. A small
premature infant whose nutrition reserve are limited can survive 4-5 days if fed water
alone and 11 days if provided with 10% dextrose alone (Brine and Ernst, 2004; Hack
and Fanaroff, 2000; Oden and Bourgeois, 2000).
PN for children is different from adults because it contains relatively more electrolytes
and other nutrients (Iacobelli et al., 2010). Prime goals of nutritional support during
first few days of postnatal life are, to maintain the liquid balance, to normalize
glycaemia and to maintain levels of electrolytes and minerals in the body. In general,
the liquid needs of large immature neonates vary from 90 to 140 mL/kg/day when they
are in radiant warmers and 80 to 120 ml/kg/day when they are in incubators. Liquids
are normally administered to immature neonates as 5% or 7.5% solutions of glucose,
to avoid glycemic disorders which are common in the first days of life (Diekmann
et.al., 2005; Falk, 1998; Jadhav et.al., 2007; Pauls et al., 1998; Ronchera-Oms et.at.,
1995).
PN is one of the major advances in neonatal medicine, and it can be used successfully
for prolonged periods in infants who cannot be fed enterally. Early use of PN can
minimize the adverse impact of multiple metabolic complication in part because it
provides multiple nutrients that may target a common metabolic function through
different metabolic pathways. (NICE Guideline, 2006; Wilmore et.al, 1968). The early
use of PN also helps to maintain an optimal nutritional states and allows the infant to
better tolerate enteral feeding, which in turn is critical to the successful weaning of the
3
infant from PN. In contrast, inadequate nutritional support may contribute to a delay
in growth over the short term (until hospital discharge) and over the long term by the
persistence of growth delay into childhood, particularly in small preterm infants
(ESPGHAN/ESPEN, 2005).
The addition of medications and other additives to PN has become common practice
in order to reduce intravenous catheter manipulations and minimizing the risk of
contamination (Atkinson 2001; Franasois et.al., 1997; McGuire et al., 2004). Above
all, data about micronutrient stability after adding medication to pediatric PN is almost
rare in the literature which is vital for the welfare of the patients especially neonates
and infants. Various issues may be related to micronutrients and macronutrients’
physical and chemical instability in PN together with medications (Forbes, 2004).
The major obstacles encountered in delivering PN and medications in neonates are
their limited intravenous access and fluid restriction. Fragile peripheral veins cannot
withstand irritating chemicals in intravenous solutions and are often exhausted in a
short period of time. The particular problem with drug therapy in infants is the
consideration of fluid volume. Multiple drugs therapy for the acutely ill infant can
account for a majority of the allowable fluid intake of the infant. When PN is used, the
natural tendency is to use it as a drug delivery vehicle so as to remain within the fluid
volume tolerance of the infant. Careful consideration must be given to the
psychochemical properties of the drug and nutrient constituents to prevent
incompatibilities and degradation or inactivation of certain nutrients in parenteral
nutrition. (Niemiee et.al, 1984; Zenk et.al 1987).
4
1.2 Parenteral Nutrition in Malaysia
Prior to early eighties, parenteral nutrition in Malaysia was provided conventionally.
Multiple nutritional solutions were hung over the patient’s bed and administered by a
multiple intravenous line. The indication for PN is mainly fluid therapy rather than as
nutritional supplement (Bahari, 1994). Parenteral nutrition in Malaysia was first
started at the Kuantan General Hospital in 1986, followed by the Penang Hospital,
Kuala Lumpur Hospital and Universiti Sains Malaysia Hospital (Bahari, 1994;
Shamsuddin et.al 1994; Bahari, 1998).
The role of pharmacists in the provision of PN services in Malaysian hospitals prior to
1986 had been very minimal. In fact, their main role was limited to the procurement
and distribution of the nutritional solutions. PN services were started in Kuantan,
Penang and Kuala Lumpur hospitals and followed by HUSM in 1987. HUSM provided
the PN services initially to the pediatric wards and later expanded the services to
include adult wards especially to surgical patients. In order to improve the role of
pharmacists, HUSM started an Aseptic Dispensing Unit (ADU) within the Pharmacy
Department in 1991 to provide a centralized PN service. The pharmacists from the
ADU worked together with physicians, nurses and dietitians as a team known as TPN
Team (Bahari, 1993).
5
1.3 Problem statement
The neonatal period is a vital interval where nutrition can influence the infant’s growth
and development. Failure to provide essential nutrients can result in serious conditions,
including growth retardation, reduced respiratory and cardiac reserve, impaired
immune system, impaired tissue and muscle functions and neurological deficits
(Sedlacek et al., 2006; Wilson et al., 1997). The period of 30 weeks of gestational age
to 6 months of life is vital for brain development while nutrition compromised in this
period may cause everlasting loss of brain development. Therefore, the nutrient
support of the preterm and critically ill infant is extremely important, not only for rapid
endurance but also for a long-term outcome (Chaudhari and Kadam, 2006, Mermel et.
al., 2001).
Intravenous drug administration in neonatal intensive care unit (NICU) and pediatric
intensive care units (PICU) is critical because of poor venous access, polymedication,
fluid restriction and low infusion rate. Risk is further increased by inadequate
information on the physicochemical compatibility of drugs. Currently, no international
guideline exists for the clinical management of drug incompatibilities. Different
decision supporting tools such as handbooks, cross-tables and databases are available
with essentially pertinent information about physical and chemical incompatibilities
(De Giorgi et.al, 2010).
Since PN is infused intravenously, it is often considered as a vehicle for medication
administration. Medication may be added to PN formulations in an effort to decrease
fluid requirements, reduce the need for Y-site injections, reduce the possibility of line
contamination due to manipulation and decrease labor time required for drug
6
administration. Although these reasons may seem compelling, the physicochemical
complexity of PN formulations makes their interactions with parenteral medications a
very challenging compatibility dilemma (Mirtallo et al., 2004).
Compatibility studies of medications with PN involve simulated 1:1 volume ratio
dilutions of drug with PN admixtures, assuming the medication is administered via
piggyback, intravenous push, or other intravenous method via the Y-site injection port
(Driscoll, 2005). Actual concern is what happens in the tubing between the PN
admixtures, Y-site, and venous catheter. A typical setback is an incompatibility that
creates a precipitate or interrupts the fat emulsion stability resulting in an occluded
catheter (Hoang et al., 2008; Kearney et.al 1998). Therefore, a drug that may appear
to be compatible may have been altered considerably and lost most of its potency this
way (Deshpande, 2003; Driscoll, 2003; Joy et al., 2010; Mirtallo, 2004).
A major disadvantage to the use of PN solutions as drug delivery vehicles is the lack
of compatibility and drugs interaction data in the PN solutions that are used commonly
in clinical practice. At present no study has been performed to develop tool or data
base on drug-drug interactions and compatibility of PN solutions commonly used by
hospital pharmacies in Malaysia.
The information necessary to address the above problem is still not available.
Although the PN service has been introduced for more than 20 years in Malaysia, the
data on the number of hospitals offering the service, the extend of pharmacists
involvement, the availability of standard solution and other related information are
7
not available in a comprehensive manner (Bahari 1999; Shamsuddin et.al 1994;
Bahari 1998; Bahari 1990; Harbans 1994; Ramanujam 1994). Drug nutrient
interaction and physicochemical compatibility of cephalosporin with parenteral
nutrition by using HPLC have been investigated (Shahid et.al 2013). Drug-nutrient
interactions result in derangements of fluid and electrolyte homeostasis, changes in
vitamin status, and disturbances of the acid-base balance. Recognition of compatibility
and these drug-nutrient interactions may assist the clinician to prevent complications
and to achieve desired therapeutics outcomes.
This study will develop and validate the database to provide compatibility information
related to drug-drug and drug-PN interaction among IV drugs commonly prescribed
in neonatal intensive care unit (NICU) patients in Malaysia setting. Development of
this database is related to extend of PN practice in Malaysian Hospitals, the role of
pharmacist and the scope of PN service. The study also will provide an evaluation of
parenteral nutrition practice and clinical outcomes of critically ill neonates in neonatal
intensive care unit Hospital Pulau Pinang.
1.4 Objectives of the Study
General objectives of the study were:
1. To develop a data base to identify the compatibility of drug-drug and drug-
parenteral nutrition in NICU
2. To evaluate current parenteral nutrition practice in Neonates at Hospital Pulau
Pinang
8
3. To validate the developed data base as a tool to check the compatibility of the
drug-drug and drug-parenteral nutrition in NICU patients.
Specific objectives of the study were:
1. To evaluate socio demographic characteristic, clinical complication,
parenteral nutrition practices and clinical outcome of the neonates
receiving parenteral nutrition and injectable drugs
2. To identify IV drugs commonly prescribed during parenteral nutrition
administration in neonate patients
3. To evaluate compatibility and clinical outcome of the neonates receiving
parenteral nutrition and injectable drugs
4. To develop a database to identify the compatibility of drug-drug and drug-
PN in NICU patients.
1.5 Hypothesis of the study
Hypothesis of the study was:
Ho: There is no association of clinical condition among neonates receiving parenteral
nutrition and injectable drugs with the compatibility of drug-drug and drug-parenteral
nutrition interaction.
9
1.6 Significance of the study
1. The study will contribute in the improvement of quality of nutritional care of
neonatal intensive care patients by reducing the risks of drug-drug and drug-nutrient
interactions of PN formulation.
2. The databases can be used to develop guideline in prevention of drug-drug or drug-
parenteral nutrition interactions.
10
CHAPTER II
LITERATURE REVIEW
2.1 Nutritional support
2.1.1 Oral nutrition
Oral supplements should be prescribed for those unable to meet their nutritional
requirements from the hospital menu. These supplements are available in a variety of
flavours such as in semi-solid or powder form, as well as cartons of liquid. Verbal
encouragement, offering a mix of flavours and giving them chilled or as a milkshake
aids compliance (ASPEN 2002).
2.1.2 Enteral Nutrition
All people need food to live, however sometimes a person cannot eat any or enough
food because of an illness while others may have a decreased appetite, difficulties in
swallowing, or some types of surgery that interferes with eating. When this occurs,
and one is unable to eat, nutrition must be supplied in a different way. One method is
“enteral nutrition” often called “tube feeding”. Tube feeding is a method in which a
special liquid food formula containing protein, carbohydrates (sugar), fats, vitamins
and minerals, is given through a tube into the stomach or small bowel. People of all
ages have received tube feeding. It may be given to infants and children, as well as to
adults. Tube feeding can be used for a short time, and then the tube is removed when
the person can begin to eat normally again. Tube feeding can be given through
different types of tubes. One type of tube can be placed through the nose into the
11
stomach or small bowel. This tube is called a nasogastric or nasoenteral feeding tube.
Sometimes the tube is placed directly through the skin into the stomach or small bowel.
This method is called a gastrostomy or jejunostomy (ASPEN 2002; ASPEN 2009).
If the patient is unable (e.g. nausea, frailty) to drink nutritional sip feeds, enteral tube
feeding should be considered. The benefits of enteral tube feeding include: nutrients
are effectively mobilized and utilized as compared to parenteral feeding, function of
the gut barrier is preserved, preventing ‘bacterial translocation’ can be prevented,
hence reducing the chance of sepsis, complications are generally less serious than
those of parenteral nutrition, and it is also cheaper and easier to manage than parenteral
nutrition. Choice of enteral tube feeds depends on: the route of nutritional support,
nutritional requirements, impairment of the gastrointestinal tract and associated
clinical conditions (e.g. renal or liver failure) (Merce et.al, 2002).
2.1.3 Parenteral Nutrition
Parenteral nutrition (PN) is intravenous administration of nutrition, which may include
protein, carbohydrate, fat, minerals and electrolytes, vitamins and other trace elements
for patients who cannot eat or absorb enough food through tube feeding formula to
maintain good nutrition status. Achieving the right nutritional intake in a timely
manner can help combat complications and be an important part of a patient’s recovery
(ASPEN 2009).
Parenteral nutrition is sometimes called Total Parenteral Nutrition (PN). People of all
ages also receive parenteral nutrition. Like tube feeding, it may be given to infants and
12
children, as well as to adults. People can live well on parenteral nutrition for as long
as it is needed. Many times, parenteral nutrition is used for a short time; then it is
lessened or discontinued when the person begins to eat normally again. Parenteral
nutrition bypasses the normal digestion in the gastrointestinal (GI) tract. It is a sterile
liquid chemical formula given directly into the bloodstream through an intravenous
(IV) catheter (needle in the vein). Patients may need PN for any variety of diseases or
conditions that impair food intake, nutrient digestion or absorption. Some diseases and
conditions where PN is indicated include but are not limited to short bowel syndrome,
GI fistulas, bowel obstruction, critically ill patients, and severe acute pancreatitis.
Some patients may require this therapy for a short time and there are other patients
who have received TPN at home for a lifetime. PN is a life-saving yet complex therapy,
which is not without risk of complications. Some of these complications include
infection, metabolic, and fluid issues. Management by an interdisciplinary Nutrition
Support Team can optimize patient outcomes associated with this therapy (ASPEN
2009; JPEN 2004).
Failure of enteral feeding is the main indication for parenteral nutrition. Enteral tube
feeding is inappropriate in proximal intestinal fistulas, intestinal obstruction or post-
chemotherapy mucositis. Total intravenous feeding is commonly used. Long-term
parenteral nutrition is well established and can be delivered at home safely and with
an excellent quality of life (JPEN, 2004)
2.1.4 Parenteral Nutrition in Adult
Parenteral nutrition refers to TPN formulations; total nutrient admixtures (TNA) are
TPN formulations that include intravenous fat emulsion (IVFE); and 2 in 1
13
formulations are TPN formulations that do not include IVFE. PN formulations are
extremely complex admixtures containing 40 or more components including both
macronutrients (carbohydrates, lipids, amino acids) and micronutrients (electrolytes,
trace minerals and vitamins). These nutrients are mixed into a bag and infused
simultaneously into the blood circulation through the peripheral or central vein.
(Maisonneuve et.al, 2004; Mirtallo et.al 2004).
PN is indicated in patients with a non-functioning digestive tract to correct or maintain
their nutritional status. They can be administered in any of the following ways: firstly,
the classic separate bottles (SB) system in which nutrients are stored in separate bottles
or bags and infused through separate intravenous (IV) lines. This system requires
numerous IV line manipulations and is associated with increased risk of administration
errors, as well as septic and metabolic complications. Secondly, the ‘all-in-one’ system
in which all nutrients are mixed in one bag and infused simultaneously. This system
requires only one IV line, thus decreasing manipulation-related and metabolic risks.
Thirdly, three-compartment bags containing macronutrients and electrolytes in three
separate compartments. Nutrients are mixed just prior to infusion, by breaking the
plastic connectors between the compartments, and then vitamins and trace elements
are added extemporaneously to the bag. The shelf-life of these bags is at least 12
months, but it is only useful for standardized formulas. PN provides life-sustaining
therapy for patients who are unable to consume conventional dietary therapy either
orally or enterally (Maisonneuve et.al 2004; Riyadh et.al, 2007).
14
Nowadays, the term PN is widely used in the literature to denote the administration of
nutrients intravenously. Basically, PN is only indicated when the oral, or enteral, route
of nutrition cannot be established (i.e. the use of the gastrointestinal system), or is
insufficient for the maintenance of the patient’s nutritional requirements in relation to
his/her clinical status. Partial parenteral nutrition is the concurrent IV administration
of nutrients together with oral or enteral nutrition for the same therapeutic objective.
The dietary components of a standard PN regimen are the macronutrients (protein or
amino acids, carbohydrates and fats), the electrolytes, the micronutrients (trace
elements and vitamins) and water. Carbohydrates, in the form of glucose or dextrose,
and lipids are the major sources of energy (Shamsuddin et.al, 2003).
2.1.5 Parenteral Nutrition in Pediatric
PN is used to treat children that cannot be fully fed by oral or enteral route, for example
due to severe intestinal failure (Wilmore et.al, 1968). Intestinal failure occurs when
the gastrointestinal tract is unable to ingest, digest and absorbs sufficient
macronutrients and/or water and electrolytes to maintain health and growth. Children
differ from adults in that their food intake must provide sufficient nutrients not only
for the maintenance of body tissues but also for growth. This is particularly true in
infancy and during adolescence when children grow extremely rapidly. At these times
children are particularly sensitive to energy restriction because of high basal and
anabolic requirements (Heird et.al 1972; Koletzko et.al, 2005).
15
The ability to provide sufficient nutrients parenterally to sustain growth in infants and
children suffering from intestinal failure or severe functional intestinal immaturity
represents one of the most important therapeutic advances in pediatrics over the last
three decades. Improvements in techniques for artificial nutritional support now ensure
that children in whom digestion and absorption are inadequate or who are unable to
eat normally no longer need to suffer from the serious consequences of malnutrition
including death. (Tsang et.al 2005; Royal College of Pediatrics and Child Health,
1997).
2.1.6 Parenteral Nutrition in Neonates
Total parenteral nutrition (PN) is the intravenous infusion of all nutrients necessary for
metabolic requirements and growth. PN refers to the supplemental intravenous
infusion of nutrients by peripheral or central vein. Enteral nutrition (EN) is provided
by oral or gavage feedings. PN is commonly indicated in neonates experiencing
congenital malformation of the gastrointestinal tract, gastroschisis, meconium and
paralytic ileus, short bowel syndrome, necrotizing enterocolitis (NEC), respiratory
distress syndrome, extreme prematurity, sepsis, and malabsorption. The ability to
provide PN over the past four decades has significantly improved the overall survival
of newborns when other options of adequate nutritional support were not possible
(Brine et.al, 2004).
The goal of PN is to initially provide sufficient nutrients to prevent negative energy
and nitrogen balance and essential fatty acid deficiency and support normal rates of
intrauterine growth of appropriate composition without increased significant
16
morbidity. Fear of toxicity and metabolic imbalance has alerted clinicians to use PN
with caution, especially in the sickest and most premature infants. An increasing
number of practitioners appreciate that this cautionary management has resulted in
suboptimal nutrition intake of these infants. Practitioners have speculated that this
cautionary practice contributed in part to national growth failure outcome statistics
published of infants extremely low in birth weight (ELBW; less than 1,000 grams) and
appropriate for gestational age (AGA; weight ≥10th percentile norm) born from 1995
to 1996. When assessed at discharge (≈ 36 weeks’ corrected age) 99% of these infants
had significant growth failure with weights less than the 10th percentile compared with
intrauterine growth standards.(Brine et.al 2004; Lemons et.al 2001) Longer-term
statistics indicate that a significant percentage of infants born very low in birth weight
(VLBW; less than 1,500 grams) may suffer substantial neurodevelopmental deficits in
part attributable to inadequate nutritional support in the neonatal period.(Hack et.al,
1999) In more recent years, the earlier introduction and more aggressive advancement
of TPN was shown to be safe and effective, even in the smallest and most immature
infants (Thureen et.al 1999; Thureen et.al, 2000; Thureen et.al 2003, Heird et.al 1999,
Poindexter et.al 2003).
Timely intervention with PN begins with the provision of glucose as soon as possible
after birth with amino acids within the first 12 hours, intravenous fat within the first
24 to 48 hours, and trophic feeding within the first 24 hours. (Wilson et.al 1997).
Optimal use of routine PN for nutritional support of ELBW and VLBW infants may
influence short-term outcomes such as lower propensity to infection and shortened
hospital stay, as well as longer-term outcomes such as decreased growth deficits
improved neurodevelopment, and overall morbidity (Hay et.al 1999; Dusick et.al,
17
1998; Vohr et .al, 2000). Indications that are generally recognized as those that
necessitate PN for newborns are listed in Table 2.1.
Table 2.1 Indications for PN Support and Route of Administration for Neonates
Who Require Intensive Care (adapted from Brine E and Ernst J (2004), Newborn
and Infant Nursing Reviews, 4, 133-155.)
Route of PN Administration Indication for PN
Peripheral
Central
Temporary supply of nutrients <2 weeks:
- Less Enteral intake
- Functional gut immaturity
- Temporary feeding intolerance
- Medical instability
Prolonged nonuse of the gastrointestinal
(GI) tract >2 weeks:
- Short bowel syndrome
- Surgical GI disorders
- Necrotizing enterocolitis
- Intractable diarrhea
- Meconium ileus
- Line access in infants extremely low
in birth weight <1,000 grams
18
2.1.7 Components of PN Solutions
PN provides some or all nutrients of basal metabolism and growth for fluid, energy,
macronutrients(protein, carbohydrate, and fat) and micronutrients (electrolytes, major
minerals, trace minerals, and vitamins) (Price et.al 2000; Anderson et.al 2000; Ziegler
et.al 1976; Peter 1997; Yardley 1992; Vileisis 1987; Schanler 2003; Krug 2000).
Recommended intakes for premature and term neonates are summarized in Table 2.2:
Table 2.2 Usual Daily Requirements of Nutrients in PN Solutions for Preterm and
Term Neonates (adapted from Brine E and Ernst J (2004), Newborn and Infant
Nursing Reviews, 4, 133-155.)
Nutrient Additive Usual Daily requirements in PN
Neonatal amino acid
Cysteine hydrochloride
Dextrose
For maintenance:
1.5-2.5 g/kg/d
For ELBW infants, begin at a minimum of 1.5 g/kg/d as soon
as possible.
Goals for growth:
3.5 g/kg/d for <1,000 grams
3.0 g/kg/d for 1,000-2,500 grams
2.5 g/kg/d for >2,500 g
4.0 g/kg/d for some infants with
greater needs
40 mg/g of amino acids (120 mg/kg maximum)
Refer to acetate guidelines for ELBW infants (see below
under Excess anions)
For maintenance:
4-6 mg/kg/min (endogenous hepatic glucose
production)
8-10 mg/kg/min (preserves carbohydrate stores)
Goals for growth: 12-13 mg/kg/min
19
Lipid (20% emulsion from
100% soy oil)
Energy
Carnitine
Heparin
Sodium (Na) as chloride or
Phosphate
Potassium (K) as chloride
or phosphate
Chloride (Cl)
Excess anions
Acetate
Chloride
Usual maximum concentration:
12.5% peripheral route
20-25% central route
0.5-4.0 g/kg/d; Begin 0.5-1.0 g/kg/d and advance by 0.5-1.0
g/kg/d
Essential fatty acids met with 1.0 g/kg/d and at least 80
kcal/kg/d
Delivered as a component to the amino acid–glucose solution
(admixture) or as a separate solution
Goals for maintenance
Preterm/term: 60 kcal/kg/d
Goals for growth
Preterm: 90-110 kcal/kg/d
Term: 80-90 kcal/kg/d
Dextrose (40-60%), lipid (40-50%), protein (10-15%)
2-10 mg/kg/d not to exceed 50 mg/kg/d
1 unit/mL not to exceed 137 units/d
0.5 unit/mL for ELBW infants when volume exceeds 150
mL/kg/d
2-4 mEq/kg/d
Positive nitrogen balance is critical
for growth; ELBW infants may
require increased intake
2-4 mEq/kg/d
Consider omitting in ELBW infants
until renal sufficiency is well
established
2-4 mEq/kg/d
Usual Na:Cl is 1:1
Excess anion equivalent = (Na+ K) - (Cl+ P)
Usually provide electrolytes as acetate Always use acetate if
adding cysteine hydrochloride for ELBW
20
Calcium (Ca) as gluconate
Phosphorus (P) as sodium
or potassium phosphate
Magnesium (Mg)
Vitamins as MVI-Pediatric
Zinc (Zn) as sulfate or in pediatric
trace element (PTE) solution
Copper (as sulfate or in PTE)
Selenium in PTE
Chromium in PTE
1-3 mEq/kg/d for maintenance
3-4.5 mEq/kg/d for growth (see text for solubility limits)
Should be administered through a central line rather than a
peripheral line in premature infants
1.3 mmol/kg/d for maintenance
1.5-2.0 mmol/kg/d for growth
0.25-1.0 mEq/kg/d
Begin ELBW infants at low end
Increased needs for infants with
ostomy losses
Premature: 2 ml/kg/day to a maximum of 5 mL/d
Term: 5 mL/d
400µg/kg/d: Preterm infants and all infants with
gastrointestinal losses
250µg/kg/d: Term infants 0-3 months
100µg/kg/d: Term infants > 3 months and all infants with
long-term TPN
Withhold during the first 2 weeks of TPN, then initiate at 20
µg/kg/day
Decrease amount or withhold with complication of
obstructive jaundice
Withhold during the first 2 weeks of TPN
Decrease amount or withhold with complication of renal
dysfunction
Premature: Begin at 1.3 µg/kg/d and advance to 1.5-2.0
µg/kg/d
Term: 2.0 µg/kg/d
Withhold during the first 2 weeks of TPN
Decrease amount or withhold with complication of renal
dysfunction
Premature: Begin at 0.05µg/kg/d and advance to 0.05-0.2
µg/kg/d
21
Manganese in PTE
Iodide (I)
Molybdenum (Mb)
Iron (Fe) as dextran or ferrous
citrate
Fluoride (Fl)
Term: 0.2 µg/kg/d
Withhold during the first 2 weeks of TPN
Decrease amount or withhold with complication of
obstructive jaundice
Premature: Begin at 0.75 µg/kg/d and advance to 1.0 µg/kg/d
Term: 1.0 µg/kg/d
Withhold for the first 3 months of TPN
Premature: 1.0µg/kg/d
Withhold for the first 3 months of TPN
Decrease amount or withhold with complication of renal
dysfunction
Premature/term: 0.25µg/d
May withhold until 2 months of age (Premature), 3 months of
age (Term) and considered for infants who do not receive
regular blood transfusions.
Premature/Term: 1.0-2.0µg/kg/d
Withhold for the first 3 months of TPN then provide premature
with 500µg/kg/d
Solutions may be contaminated with fluoride
Zinc is unanimously suggested from day one of PN therapy, while the rest trace
minerals are commonly administered after three, five, or twelve weeks of PN without
any significant enteral feeding (Hardy et al., 2001). Zinc requirements are increased in
metabolic stress secondary to increased urinary losses and in gastrointestinal disease
secondary to ostomy or diarrheal losses. ELBW infants need additional zinc than term
infants (Pluhator-Murton et al., 1999). Selenium stores have been revealed to be
depleted in patients receiving long-term parenteral nutrition or in those with thermal
injury, acquired immunodeficiency syndrome, or liver failure. Therefore, selenium
should be added initially to the parenteral nutrition solution for patients with these
22
disease states or conditions (Dworkin, 1994; Hardy et al., 2001; Hunt et al., 1984;
Pluhator-Murton et al., 1999). Recommended intravenous intake of trace elements for
neonates and infants has been shown in Table 2.2.
Parenteral iron supplementation may be delayed until two months of age in premature
infants and three months of age in term infants but it can be considered for those infants
who do not receive regular blood transfusions. Supplementation of iodide in PN may
not be necessary because iodide needs may be met by other routine usages of topical
iodide-containing disinfectants, detergents and other environmental sources (Al-Saleh
et al., 2005; Baptista et al., 1984; Blazewicz et al., 2010; Ekin et al., 2003; Leung,
1995; Leung, 1998; Leung et al., 1995; Ono et al., 1995; Papageorgiou et al., 2002;
Rahman et al., 2009; Yanik et al., 2004)
2.1.7 (a). Fluid
On day one of life, maintenance of fluids are met with arrangement between 80 and
140 mL/kg/d if the environment of the baby increases insensible water losses and 60
to 100mL/kg/d in environments with increased humidity. Thereafter, fluid volume is
advanced as tolerated to 120 to180 mL/kg/d. Maximal fluid volume varies with
individual management (Anderson 2000).
2.1.7 (b). Macronutrients
Carbohydrate (dextrose) and fat (lipid emulsions) provide the energy needed to meet
the demands of the circulatory, respiratory, neurological, and muscular systems and,
23
when provided in adequate amounts, spare protein(amino acids) to support cell
maturation, remodeling, growth, activity of enzymes, and transport proteins for all
body organs. Energy needs may be increased with infection, chronic lung disease,
healing, growth, and in neonates who have experienced intrauterine growth restriction
(IUGR). Energy needs may be decreased with sedation, mechanical ventilation, and
after tracheotomy placement.
The use of PN is suggested to support all ill and premature neonates less than 1,500
grams that cannot sustain at least ~60 kcal/kg/d enterally and initiation
isrecommended during the first 24 hours of life to avoidexcessive protein losses. The
premature infant who is not growing, not septic, and not unduly stressed requires an
energy intake of about 50 kcal/kg/d for resting energy expenditure, activity, and
occasional cold stress, (Denne et.al 2002; Leitch et.al 2000; Zlotkin et.al 1981; Bell
1996) with as little as ~1 to 1.5 g protein/kg/d to preserve endogenousprotein stores
(Thureen et.al 2003; Ziegler 1994; Thureen et.al 1998). At least 60 kcal/kg/d is thought
to meet energy requirements during acute sepsis (Premer et.al 1999).
(i). Carbohydrate
Carbohydrate is delivered in 2.5 to 70% dextrose solutions that provide 3.4 kcal/g.
Glucose is the energy source for all cells and is essential for the central nervous system
(CNS), erythrocytes, and other tissues. To ensure a stressed premature infant receives
an adequate but not excessive amount of glucose, the amount of carbohydrate
delivered in the form of dextrose is commonly initiated at the endogenous hepatic
glucose production and utilization rate of 4 to 6 mg/kg/min (Denne et.al 1986) 8 to 10
24
mg/kg/min in ELBW infants provides 40 to 50kcal/kg/d and preserves carbohydrate
stores (Hertz et.al 1993).
Frequently smaller, more unstable premature infants develop hyperglycemia due to
decreased insulin production and insulin resistance. Glucose infusion rates (GIR) for
these neonates may need to be limited to 4 mg/kg/min or less, while larger preterm
infants or term infants can often tolerate up to 8 mg/kg/min initially (Denne et.al 2002;
Lifshitz 1988). Once the GIR supports acceptable serum glucose values, it is advanced
in a gradual, stepwise fashion (0.5 to 1 mg/kg/min) to a suggested maximum glucose
oxidative rate for neonates of 12 to 13 mg/kg/min to support growth and maintained
there unless serum glucose values change significantly (Reiter et.al 2001; Baker et.al
1997).
In most situations, a glucose concentration above12.5% is not necessary (Denne et.al
2002). However a higher glucose concentration may be needed when fluid intake is
severely restricted or when the amounts of protein and/or fat are limited (Denne et.al
2002). Excessive carbohydrate delivery above the amount that can be oxidized for
energy and glycogen storage will lead to an increase in basal metabolic rate (Kanarek
et.al 1991) fat deposition, cholestasis (Henry, 2003), hepatic steatosis (Shulman 2000)
or over feeding as described by the provision of energy in excess of needs for normal
growth (Shulman 2000). GIR greater than 26 mg glucose/kg/min may contribute to
infiltrates of fat in the liver (Pediatric Nutrition Handbook 2004).